Project Summary ? Technical Mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This induced pluripotent stem (iPS) cell has unquestionable clinical potential. However, adult cells must first be completely de-differentiated to an embryonic stem (ES) cell-like state, and then subsequently re-differentiated to an adult cell-type of interest---a time-consuming and inefficient detour. We have successfully generated human neural stem cells (NSCs) directly from adult fibroblasts and olfactory epithelial cells. We propose to utilize the human NSCs to regenerate damaged brain tissue. We will use a radiation treatment (RT) for lethal brain tumor, glioblastoma multiform (GBM), as a model system. GBM patients receive RT, however, tumors always recur. The cognitive dysfunctions after irradiation affect patient's quality of life. We hypothesize that higher doses of irradiation will prevent recurrence, and cognitive dysfunctions after the aggressive RT can be prevented by regeneration of damaged tissues by human NSCs. NSCs generated from adult cells are no tumorigenic unlike ESCs and iPSs. Therefore, this proposed strategy has great potential to successfully treat brain damage with low risk and low cost.